Modeling Alveolar Soft Part Sarcomagenesis in the Mouse: A Role for Lactate in the Tumor Microenvironment

Matthew L. Goodwin; Huifeng Jin; Krystal Straessler; Kyllie Smith-Fry; Ju Fen Zhu; Michael J. Monument; Allie Grossmann; R. Lor Randall; Mario R. Capecchi; Kevin B. Jones

doi:10.1016/j.ccell.2014.10.003

Modeling Alveolar Soft Part Sarcomagenesis in the Mouse: A Role for Lactate in the Tumor Microenvironment

Matthew L. Goodwin, Huifeng Jin, Krystal Straessler, Kyllie Smith-Fry, Ju Fen Zhu, Michael J. Monument, Allie Grossmann, R. Lor Randall, Mario R. Capecchi, Kevin B. Jones

Research output: Contribution to journal › Article › peer-review

42 Scopus citations

Abstract

Alveolar soft part sarcoma (ASPS), a deadly soft tissue malignancy with a predilection for adolescents and young adults, associates consistently with t(X;17) translocations that generate the fusion gene ASPSCR1-TFE3. We proved the oncogenic capacity of this fusion gene by driving sarcomagenesis in mice from conditional ASPSCR1-TFE3 expression. The completely penetrant tumors were indistinguishable from human ASPS by histology and gene expression. They formed preferentially in the anatomic environment highest in lactate, the cranial vault, expressed high levels of lactate importers, harbored abundant mitochondria, metabolized lactate as a metabolic substrate, and responded to the administration of exogenous lactate with tumor cell proliferation and angiogenesis. These data demonstrate lactate's role as a driver of alveolar soft part sarcomagenesis.

Original language	English (US)
Pages (from-to)	851-862
Number of pages	12
Journal	Cancer cell
Volume	26
Issue number	6
DOIs	https://doi.org/10.1016/j.ccell.2014.10.003
State	Published - Dec 8 2014
Externally published	Yes

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1016/j.ccell.2014.10.003

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title = "Modeling Alveolar Soft Part Sarcomagenesis in the Mouse: A Role for Lactate in the Tumor Microenvironment",

abstract = "Alveolar soft part sarcoma (ASPS), a deadly soft tissue malignancy with a predilection for adolescents and young adults, associates consistently with t(X;17) translocations that generate the fusion gene ASPSCR1-TFE3. We proved the oncogenic capacity of this fusion gene by driving sarcomagenesis in mice from conditional ASPSCR1-TFE3 expression. The completely penetrant tumors were indistinguishable from human ASPS by histology and gene expression. They formed preferentially in the anatomic environment highest in lactate, the cranial vault, expressed high levels of lactate importers, harbored abundant mitochondria, metabolized lactate as a metabolic substrate, and responded to the administration of exogenous lactate with tumor cell proliferation and angiogenesis. These data demonstrate lactate's role as a driver of alveolar soft part sarcomagenesis.",

author = "Goodwin, {Matthew L.} and Huifeng Jin and Krystal Straessler and Kyllie Smith-Fry and Zhu, {Ju Fen} and Monument, {Michael J.} and Allie Grossmann and Randall, {R. Lor} and Capecchi, {Mario R.} and Jones, {Kevin B.}",

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T2 - A Role for Lactate in the Tumor Microenvironment

AU - Goodwin, Matthew L.

AU - Jin, Huifeng

AU - Straessler, Krystal

AU - Smith-Fry, Kyllie

AU - Zhu, Ju Fen

AU - Monument, Michael J.

AU - Grossmann, Allie

AU - Randall, R. Lor

AU - Capecchi, Mario R.

AU - Jones, Kevin B.

PY - 2014/12/8

Y1 - 2014/12/8

N2 - Alveolar soft part sarcoma (ASPS), a deadly soft tissue malignancy with a predilection for adolescents and young adults, associates consistently with t(X;17) translocations that generate the fusion gene ASPSCR1-TFE3. We proved the oncogenic capacity of this fusion gene by driving sarcomagenesis in mice from conditional ASPSCR1-TFE3 expression. The completely penetrant tumors were indistinguishable from human ASPS by histology and gene expression. They formed preferentially in the anatomic environment highest in lactate, the cranial vault, expressed high levels of lactate importers, harbored abundant mitochondria, metabolized lactate as a metabolic substrate, and responded to the administration of exogenous lactate with tumor cell proliferation and angiogenesis. These data demonstrate lactate's role as a driver of alveolar soft part sarcomagenesis.

AB - Alveolar soft part sarcoma (ASPS), a deadly soft tissue malignancy with a predilection for adolescents and young adults, associates consistently with t(X;17) translocations that generate the fusion gene ASPSCR1-TFE3. We proved the oncogenic capacity of this fusion gene by driving sarcomagenesis in mice from conditional ASPSCR1-TFE3 expression. The completely penetrant tumors were indistinguishable from human ASPS by histology and gene expression. They formed preferentially in the anatomic environment highest in lactate, the cranial vault, expressed high levels of lactate importers, harbored abundant mitochondria, metabolized lactate as a metabolic substrate, and responded to the administration of exogenous lactate with tumor cell proliferation and angiogenesis. These data demonstrate lactate's role as a driver of alveolar soft part sarcomagenesis.

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Modeling Alveolar Soft Part Sarcomagenesis in the Mouse: A Role for Lactate in the Tumor Microenvironment

Abstract

ASJC Scopus subject areas

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